1. Field of the Invention
The invention herein related to the treatment of bile acid deficiency states and to improvement of the composition of the circulating bile acids. It also relates to synthetic bile acids for such uses.
2. Background and Prior Art
Natural bile acids are the water-soluble end products of cholesterol metabolism in most mammals. Bile acids, in the form of their anions, also function as biological surfactants which form mixed micelles and thereby promote lipid transport.
After their biosynthesis from cholesterol, natural bile acids are conjugated with the amino groups of glycine or taurine (in N-acyl linkage) by hepatic enzymes; the resultant conjugated bile acids are secreted into bile. In bile, bile acids form mixed micelles with phospholipid and cholesterol, solubilizing cholesterol and permitting its excretion into the small intestine from which it is poorly absorbed. In the small intestine, bile acids form mixed micelles with monoglycerides and fatty acids--the products of digestion of dietary triglyceride--accelerating their absorption. The solubilization of fat soluble vitamins in mixed micelles is essential for their absorption. Conjugated bile acids are not hydrolyzed during their transit down the small intestine, since the amide bond between the carboxyl group of the bile acid and the amino group of the glycine or taurine is resistant to pancreatic carboxypeptidases.
Bile acids are actively and efficiently absorbed by the terminal small intestine. Their efficient absorption leads to a large recirculating mass of bile acids, called the "bile acid pool."
For bile acids to form mixed micelles with lipids such as fatty acids and monoglycerides (the digestive products of dietary triglyceride), bile acids must be above a critical concentration, termed the critical micellization concentration ("CMC"). When bile acids are present at a concentration below the CMC, defective solubilization of lipolytic products and 17 fat soluble vitamins occurs, causing their malabsorption. Bile acid deficiency occurs when the ileal absorption of bile acids is impaired because of ileal dysfunction (such as might occur in inflammatory disease of the ileum, e.g. Crohn's disease) or resection of the ileum. Bile acid deficiency can also occur because of lack of secretion of bile acids into the proximal small intestine--either because of obstruction of the biliary tract or diversion of the biliary tract to the outside (biliary fistula). Bile acid deficiency can also occur in the small intestine when there is bacterial overgrowth; bacteria deconjugate the bile acids forming the parent compounds, unconjugated bile acids. These unconjugated bile acids, being weaker acids and more lipophilic molecules, can be absorbed rapidly (passively) when formed or may precipitate from solution as the insoluble protonated acid.
There is thus a need to replace bile acids in conditions of bile acid deficiency to restore the absorption of fat and fat-soluble vitamins to normal. There is also a potential need to replace bile acids in biliary fistula patients who require lipid-soluble drugs, for example, liver transplant patients who require cyclosporin.
Previous attempts to replace bile acids have used either a pure conjugated bile acid such as taurocholate (cholyltaurine), an unconjugated bile acid such as ursodeoxycholic acid, or desiccated ox or sheep bile. A second approach has 17 been to use a synthetic non-ionic detergent.
None of these have proved very satisfactory. For any bile salt, the amount to be administered must be large--since the amount of bile salts secreted per meal is 4-6 grams.
If unconjugated bile acids are administered, they are insoluble at intestinal pH, and must be absorbed, conjugated by the liver and resecreted into bile (in conjugated form) before they are effective. The major problem with replacement therapy using animal bile preparations or conjugates of cholic acid is that administered natural bile samples contain dihydroxy bile acids which induce the colon to secrete, that is, they are cathartic. In addition, cholic acid derivatives are biotransformed to deoxycholic acid in the colon by bacterial 7-dehydroxylation, and the resultant deoxycholic acid is a potent secretory agent. Thus, when a pure conjugated derivative of cholic acid or sheep or ox bile is administered, even if steatorrhea is improved, diarrhea is worsened; the patient does not feel better. The one exception to this is the patient with an ileostomy. Here, administered bile acids can enhance the absorption of fat, yet not induce colonic secretion, because there is no colon.
Additional background of the present discovery includes studies of the physicochemical events in fat digestion and absorption, as well as the structural requirements for the induction of colonic secretion by bile acids. It has been shown that the nature of the amino acid present in bile acid conjugates determines the susceptibility of bile acid conjugates to bacterial deconjugation. For example, d-amino acid conjugates are not hydrolyzed by cholylglycine hydrolase, N-methyl glycine (sarcosine) conjugates of a number of common bile acids are not hydrolyzed by cholylglycine hydrolase in vivo, the sarcosine conjugates of ursodeoxycholic acid are not hydrolyzed in vivo. and cholylsarcosine is not hydrolyzed during enterohepatic cycling in rodent species. The significance of the resistance to hydrolysis is that the unhydrolyzed compound does not undergo 7-hydroxylation, and therefore is not biotransformed by bacterial enzymes into a secretory agent.